title: Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis.
abstract: Vascular injury that results in proliferation and dedifferentiation of vascular smooth muscle cells (SMCs) is an important contributor to restenosis following percutaneous coronary interventions or plaque rupture. Protease-activated receptor-1 (PAR1) has been shown to play a role in vascular repair processes; however, little is known regarding its function or the relative roles of the upstream proteases thrombin and matrix metalloprotease-1 (MMP-1) in triggering PAR1-mediated arterial restenosis. The goal of this study was to determine whether noncanonical MMP-1 signaling through PAR1 would contribute to aberrant vascular repair processes in models of arterial injury. A mouse carotid arterial wire injury model was used for studies of neointima hyperplasia and arterial stenosis. The mice were treated post-injury for 21 days with a small molecule inhibitor of MMP-1 or a direct thrombin inhibitor and compared with vehicle control. Intimal and medial hyperplasia was significantly inhibited by 2.8-fold after daily treatment with the small molecule MMP-1 inhibitor, an effect that was lost in PAR1-deficient mice. Conversely, chronic inhibition of thrombin showed no benefit in suppressing the development of arterial stenosis. Thrombin-PAR1 signaling resulted in a supercontractile, differentiated phenotype in SMCs. Noncanonical MMP-1-PAR1 signaling resulted in the opposite effect and led to a dedifferentiated phenotype via a different G protein pathway. MMP-1-PAR1 significantly stimulated hyperplasia and migration of SMCs, and resulted in down-regulation of SMC contractile genes. These studies provide a new mechanism for the development of vascular intimal hyperplasia and suggest a novel therapeutic strategy to suppress restenosis by targeting noncanonical MMP-1-PAR1 signaling in vascular SMCs.
authors.affiliation: Hemostasis and Thrombosis Laboratory, Molecular Oncology Research Institute, Tufts Medical Center, the Program in Genetics at the Sackler School of Biomedical Sciences, Tufts University, Massachusetts 02111, USA.
authors.forename: Karyn M
authors.initials: KM
authors.lastname: Austin
authors.forename: Nga
authors.initials: N
authors.lastname: Nguyen
authors.forename: Golrokh
authors.initials: G
authors.lastname: Javid
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000818:Animals; D016893:Carotid Stenosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D054337:Cell Dedifferentiation; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006965:Hyperplasia; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D011480:Protease Inhibitors; D044463:Receptor, PAR-1; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Cardiovascular Disease; Cell Differentiation; Matrix Metalloproteinase (MMP); PAR1; Smooth Muscle; Thrombin